Process for preparing Δ22 -25-oxy substituted sterol derivatives

ABSTRACT

A new method of preparing 3α,5α-cyclo-6β-alkoxy-Δ 22  -25-oxy or acyloxy bisnorcholestane and analogues which involves reacting a bisnorcholanaldehyde with an ylide. Novel cholestanes and i-ethers are also claimed.

BRIEF DESCRIPTION OF THE INVENTION

A new method for synthesizing 3α,5α-cyclo-6β-alkoxy-25-hydroxy andacyloxy sterol derivatives has been discovered. These sterols areintermediates in the production of 25-hydroxy cholesterol derivativesand thence 25-hydroxy Vitamin D metabolites and their analogues.

This new method comprises stereospecifically reacting an ylide ##SPC1##

Wherein A is the portion of a Wittig reagent inert to the reactionmedium, and R¹, R² and R³ are each selected from hydrogen and methyl andD is selected from the group consisting of O ⁻ ##STR1## wherein R⁴ isselected from the group consisting of alkyl of one to six carbon atoms,phenyl, benzyl, and phenethyl, with3α,5α-cyclo-6β-alkoxybisnorcholanaldehyde, alkoxy of one to six carbonatoms, inclusive, to form compounds ##SPC2## wherein R is alkyl of oneto six carbon atoms, inclusive, and R¹, R², R³ and D are defined asabove.

A further aspect of the invention is the preparation of a betaine whichcomprises reacting the methylene phosphorane

    AP=CH.sub.2                                                FIG. III

wherein A is the portion of a Wittig reagent inert to the reactionmedium, with the epoxide ##SPC3##

Wherein R¹, R² and R³ are each selected from hydrogen and methyl to form##SPC4##

Further aspects of the invention are novel cholestanes and i-ethers.

DETAILED DESCRIPTION OF THE INVENTION

The phrase "alkyl of one to six carbon atoms, inclusive" covers methyl,ethyl, propyl, butyl, pentyl, hexyl and isomers thereof. Examples ofisomers are isopropyl, tert.-butyl, neopentyl and 2,3-dimethylbutyl.

The betaine of FIG. V is prepared from the reaction of amethylenephosphorane, FIG. III, with an epoxide of FIG. IV. The A groupof the phosphorane is a group commonly employed in a Wittig reagent,see, for example, Tripett, Quart. Rev. XVII, No. 4, p. 406 (1963), andHouse, "Modern Synthetic Reactions" second edition, p. 682-709.Additionally, the group should be substantially inert with respect tothe reaction medium. Examples of such groups include triphenyl,triphenyl substituted with one to three alkyl groups on each phenyl,each alkyl group being the same or different and having from one to fourcarbon atoms, inclusive. Additionally, A can be a monosubstituted phenylwith two unsubstituted phenyls, for example, (phenyl)₂, p-carboxyphenyl.Other phosphoranes which can be used include thedimethylaminoethylenephosphorane, that is, (Me₂ N)₃ P=CH₂.

The phosphorane and the epoxide are reacted at room temperature or anyconvenient temperature of from about 0° to about 40° C. although higheror lower temperature can be employed at times. An inert organic solventis used as well. See Tripett and House, supra, for suitable solvents.Examples of such solvents include tetrahydrofuran, diethyl ether,hexane, pentane, benzene, heptane, octane, toluene, and dioxane.

Once the betaine is prepared, it is converted to the ylide, FIG. I, byconventional reagents and conditions, for example, by contact with astrong base. Illustrative of the reagents which can be employed toconvert to betaine to the ylide are the organo-lithium reagents, such asthe alkyl lithium reagents of one to four carbon atoms, sodamide, sodiumhydride, lithium amides and so forth. Art-recognized conditions are usedfor this reaction. The preferred reagent is n-butyl lithium.

The ylide of FIG. I where D is 0⁻ is then contacted with the3α,5α-cyclo-6β-alkoxybisnorcholanaldehyde to form a compound of FIG. IIwherein D is 0⁻. The temperature at which this reaction occurs is notunduly significant. Temperature of from about 0° to about 40° C. can beemployed. The preferred temperature range is from about 15° to about 25°C. It should be noted that the cation is the metal portion of the baseemployed to convert the betaine to the ylide.

To prepare compounds of FIG. I where D is ##STR2## the betaine of FIG. Vis acylated with the desired R⁴ acylating agent. For example, an R⁴ acidanhydride, or and R⁴ acyl halide, preferably chloride, are readilyemployed at standard reaction conditions. The resulting salt is thenreacted with a strong base such as lithium diisopropylamide to form theylide of FIG. I (D=acyloxy). This is then reacted with thebisnorcholanaldehyde to form a compound of FIG. II wherein D is ##STR3##Alternatively, these compounds of FIG. II wherein D is ##STR4## areprepared by reacting the ylide wherein D is 0⁻ with thebisnorcholanaldehyde and then reacting the resulting 25-oxyanionicsteroid with an acylating agent similar to that used earlier, therebyforming the i ether with D as ##STR5##

The above i-ethers can be readily converted to 25-hydroxy-cholesteroland thence to 25-hydroxycholecalciferol.

After compounds of FIG. II are prepared, the double bond between C²² andC²³ can be saturated by conventional means thereby preparing theintermediate to 25-hydroxy Vitamin D₃ and analogues, see Formula VI.##SPC5##

R, r¹, r², r³, and D defined as above.

A suitable saturation method is catalytic hydrogenation. Thehydrogenation is carried out with a noble metal catalyst in a suitableinert organic solvent at appropriate pressures. Platinum or palladiumare preferred noble metals. Inert organic solvents such as ethylacetate, methylene chloride and tetrahydrofuran can be employed. Ethylacetate is preferred. Any hydrogenation pressure which brings about areasonable rate of reaction can be used. Pressures as low as 15 psi canbe employed. The upper limit of pressure is dependent upon the loss ofyield from the opening of the cyclopropane ring. Pressure up to about100 psi or even higher can be employed with facility.

Following are examples illustrative of the invention scope. Theseexamples are meant to exemplify and not to narrow the invention.

Example 1 3α,5α-cyclo-6β-methoxy-25-hydroxy-26,27-bisnorcholest-22-ene

Methyltriphenylphosphonium bromide (17.9 g.) is stirred under nitrogenin 150 ml. tetrahydrofuran containing 15 ml. hexamethylphosphorictriamide. n-Butyl lithium (35 ml. of a 1.5M solution in hexane) is addeddropwise to yield a bright red solution. This solution is left for 30minutes before ethylene oxide (ca. 5.0 g.) is added. The reaction vesselis then sealed and the temperature raised to 35° C. for 1 hour. Afterthis time the nitrogen inlet is replaced and the reaction vessel purgedwith nitrogen to remove the excess ethylene oxide. At this point thereaction mixture is pale yellow. A further 35 ml. of n-butyl lithium isadded. This causes a bright red color to be formed, and as the additioncontinues the temperature rises to 35° C. Fifteen minutes after theaddition is completed, a solution of3α,5α-cyclo-6β-methoxybisnorcholanaldehyde (17.0 g. in 150 ml. hexane)is added dropwise until all the color of the ylide is removed. Thereaction mixture is then quenched with water and extracted with ethylacetate. The residue after evaporation and chromatography on neutralalumina gives the desired product as plates recrystallized fromacetonitrile, m.p. 104°-105° C.

Nmr (cdcl₃):

0.3-0.67m; 0.73s (3H); 1.01s (3H); 1.01d,

J=6hz, (3H); 2.77 b.t. (1H); 3.30s (3H);

3.60 t, J-6Hz (2H); 5.37m (2H).

R_(f) : (5% CH₃ OH/CHCl₃) 0.58

Example 2 3α,5α-cyclo-6β-methoxy-25-hydroxy-26,27-bisnorcholestane TheΔ²² compound (2.0 g.) obtained from Example 1 is dissolved in 40 ml.methylene chloride. 5% Platinum on carbon catalyst (0.5 g.) is added andthe mixture hydrogenated at 90 psi for 2 hours. The catalyst is filteredoff and evaporation of the filtrate yields a crystalline residue,recrystallized from acetonitrile by displacement of methylene chlorideto give needles, m.p. 128°-129° C.

Nmr (cdcl.sub. 3):

0.3-0.67m; 0.73s (3H); 1.01s (3H); 2.77b.t. (1H); 3.30s (3H); 3.60 t,J=6Hz, (2H). R_(f) : (5% CH₃ OH/CHCl₃) 0.52

Example 3 3α,5α-cyclo-6β-methoxy-Δ²² -25-acetoxy, cholestane

To a stirred suspension of methyltriphenylphosphonium bromide (3.57 g.)in dry tetrahydrofuran (30 ml.) is added at room temperature and under ablanket of nitrogen a solution of n-butyl lithium in hexane (15%, 6.3ml.). Stirring is continued for 30 minutes and then excess isobutyleneoxide added. After 1 hour the flask is purged with a stream of nitrogento remove the excess oxide and then one molar proportion of aceticanhydride is added. After fifteen minutes a solution of lithiumdiisopropylamide in hexane, prepared from 6.3 ml. of a 15% solution ofn-butyl lithium in hexane and 1.1 g. diisopropylamine in 10 ml. hexane,is added, followed thirty minutes later by a solution of 3.4 g. of thebisnorcholanaldehyde in 25 ml. hexane. After yet a further thirtyminutes the mixture is poured into methanol and worked up as in Example1 to yield the 3α,5α-cyclo-6β-methoxy-25-acetoxy, cholest-22-ene.

Example 4 3α,5α-cyclo-6β-methoxy-25-acetoxycholest-22-ene

To a stirred suspension of methyltriphenylphosphonium bromide (3.57 g.)in dry tetrahydrofuran (30 ml.) is added at room temperature and under ablanket of nitrogen a solution of n-butyl lithium in hexane (15%, 6.3ml.). Stirring is continued for 30 minutes and then excess ofisobutylene oxide is added. After one hour the flask is purged with astream of nitrogen to remove the excess oxide and then a further 6.3 ml.of the n-butyl lithium solution added. After thirty minutes a solutionof bisnorcholanaldehyde in hexane (3.40 g. in 30 ml.) is added. After afurther 15 minutes, 1.4 ml. acetic anhydride is added. After yet afurther 30 minutes the mixture is poured into methanol, and SkellysolveB (ca 200 ml.) is added followed by ca. 20 ml. water. This causes twolayers to form, the lower layer containing predominantly the by-producttriphenyl phosphine oxide, and the upper layer containing the desired25-acetate. Drying of the upper layer followed by evaporation yields aresidue of the desired 3α,5α-cyclo-6β-methoxy-25-acetoxycholest-22-ene.

Nmr (cdcl.sub. 3):

δ0.75s (3H); 1.03s (3H); 1.40s (6H); 1.93s (3H); 2.77m (1H); 3.20s (3H);5.30m (2H).

Example 5 3α,5α-cyclo-6β-methoxy-25-benzoxycholest-22-ene

In a fashion directly analogous to that described in Example 4 butreplacing the acetic anhydride by benzoyl chloride, there is obtainedthe compound 3α,5α-cyclo-6β-methoxy-25-benzoxy-cholest-22-ene.

The Δ^(22E) compound has the NMR (CDCl.sub. 3): δ0.27-0.70m (3H); 0.70s(3H); 0.97d, J=6Hz, (3H); 1.02s (3H); 1.55s (6H); 2.50-2.67m (1H); 2.77t(1H); 3.30s (3H); 5.20-5.50m (2H); 7.23- 7.63m (3H); 7.87-8.17m (2H).

The Δ^(22Z) compound has the NMR (CDCl.sub. 3): δ0.27-0.73m (3H); 0.78s(3H; 0.97d, J=6, (3H); 1.03s (3H); 1.58s (6H); 2.67-2.87m (2H); 3.32s(3H); 5.2-5.47m (2H); 7.2-7.58m (3H); 7.88-8.13m (2H).

Example 6

In an analogous manner to Examples 1 through 5 the followingillustrative compounds can be prepared.

    ______________________________________                                        1)   R.sup.1 =H, R.sup.2 =R.sup.3 =CH.sub.3                                                       precursor to the compound                                                     claimed in U.S.P. 3,786,062                               2)   R.sup.1 =R.sup.2 =R.sup.3 =CH.sub.3                                                          precursors to 25-OH-D.sub.2                                                   derivatives                                               3)   R.sup.1 =H, R.sup.2 =R.sup.3 =CH.sub.3                                                       precursor to 25-HCC                                       ______________________________________                                    

Example 7

In a manner similar to Examples 1 through 6, compounds where R isillustratively ethyl, propyl, butyl, pentyl, hexyl, isopropyl,tert.butyl, neopentyl, and 2,3-dimethylbutyl are prepared where R¹, R²,and R³ are each hydrogen or methyl.

Example 8

In a similar manner to Examples 1 through 7, compounds where R ispropionoxy, tert.butoxy, hexoxy, phenylacetoxy, and 2' phenylpropionoxyare readily prepared.

I claim:
 1. A method for preparing Δ²² -25-oxy substituted sterolderivatives which comprises reacting an ylide ##SPC6##wherein A is theportion of a Wittig reagent of the type AP=CH₂ and is inert to thereaction medium, R¹, R² and R³ are each selected from hydrogen andmethyl, and D is 0^(-or) ##EQU1## wherein R⁴ is selected from the groupconsisting of alkyl of one to six carbon atoms, inclusive, phenyl,benzyl and phenethyl with a 3α,5α-cyclo-6β-alkoxybisnorcholanaldehydewherein alkoxy is from one to six carbon atoms, inclusive, to formcompounds of the structure ##SPC7## wherein R is alkyl of one to sixcarbon atoms, inclusive, and R¹, R², R³ and D are as defined above.
 2. Amethod in accordance with claim 1 wherein A is selected from the groupconsisting of triphenyl, triphenyl substituted with one to three alkylgroups on each phenyl; each alkyl group being the same or different andhaving from one to four carbon atoms, inclusive, diphenylp-carboxyphenyl, and trisdialkylamino with alkyl of one to three carbonatoms, inclusive.
 3. A method in accordance with claim 1 wherein R¹, R²and R³ are each hydrogen.
 4. A method in accordance with claim 1 whereinR is alkyl of one to three carbon atoms, inclusive.
 5. A method inaccordance with claim 1 wherein R¹ is hydrogen and R² and R³ are methyl.6. A method in accordance with claim 1 wherein the ylide of claim 1, Dbeing 0⁻, is prepared bya. reacting AP=CH₂, said A portion inert to thereaction medium, with the epoxide ##SPC8##R¹, r² and R³ each selectedfrom hydrogen or methyl to form the betaine ##SPC9## b. converting thebetaine of Step a to the corresponding oxyanionic ylide.
 7. A method inaccordance with claim 6 wherein R¹, R² and R³ are each hydrogen.
 8. Amethod in accordance with claim 6 wherein R¹ is hydrogen and R² and R³are each methyl.
 9. A method in accordance with claim 1 wherein theylide of claim 1, D being ##STR6## is prepared by a. reacting AP=CH₂wherein A is the portion of a Wittig reagent inert to the reactionmedium, with the epoxide ##SPC10##wherein R¹ R² and R³ are each selectedfrom hydrogen or methyl to form compounds of the structure ##SPC11##wherein D is 0 ⁻ b. acylating D to form salts wherein D is ##STR7##wherein R⁴ is selected from the group consisting of alkyl of one to sixcarbon atoms, inclusive, phenyl, benzyl, and phenethyl, c. convertingthe salt of Step b to the ylide.
 10. A method in accordance with claim 9wherein R¹, R² and R³ are hydrogen.
 11. A method in accordance withclaim 9 wherein R¹ is hydrogen and R² and R³ are each methyl.
 12. Acompound of the formula ##SPC12##wherein R is alkyl of one to six carbonatoms, inclusive, R¹, R² and R.sup. 3 are the same or different and arehydrogen or methyl, D is selected from the group consisting of 0⁻ and##EQU2## wherein R⁴ is selected from the group consisting of alkyl ofone to six carbon atoms, inclusive, phenyl, benzyl, and phenethyl.